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https://www.readbyqxmd.com/read/28102564/pkn2-is-essential-for-mouse-embryonic-development-and-proliferation-of-mouse-fibroblasts
#1
Sally Danno, Koji Kubouchi, Mona Mehruba, Manabu Abe, Rie Natsume, Kenji Sakimura, Satoshi Eguchi, Masahiro Oka, Masanori Hirashima, Hiroki Yasuda, Hideyuki Mukai
PKN2, a member of the protein kinase N (PKN) family, has been suggested by in vitro culture cell experiments to bind to Rho/Rac GTPases and contributes to cell-cell contact and cell migration. To unravel the in vivo physiological function of PKN2, we targeted the PKN2 gene. Constitutive disruption of the mouse PKN2 gene resulted in growth retardation and lethality before embryonic day (E) 10.5. PKN2(-/-) embryo did not undergo axial turning and showed insufficient closure of the neural tube. Mouse embryonic fibroblasts (MEFs) derived from PKN2(-/-) embryos at E9...
January 19, 2017: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
https://www.readbyqxmd.com/read/28102464/a-phase-i-and-pharmacokinetic-study-of-afilbercept-with-folfiri-comparison-of-chinese-and-caucasian-populations
#2
Jianming Xu, Yingxin Li, Xing Sun, Dongsheng Zhang, Rongrui Liu, Samira Ziti-Ljajic, Dongmei Shi, Fengying Xue, Nathalie Le Bail, Ruihua Xu
Background This study assessed the preliminary safety, pharmacokinetics (PK) and anti-tumor effects of aflibercept in combination with 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) in Chinese patients with previously-treated advanced solid malignancies. Patients and Methods This open-label single-arm Phase I study conducted at two centers in China included adult (≥18 years) patients with metastatic or unresectable solid malignancies who had received ≥1 prior treatment. Patients received aflibercept 4 mg/kg IV on Day 1 followed by FOLFIRI over Days 1 and 2 every 2 weeks, and were assessed for safety, tumor response, PK parameters and immunogenicity...
January 19, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28099152/the-emsy-threonine-207-phospho-site-is-required-for-emsydriven-suppression-of-dna-damage-repair
#3
Petar Jelinic, Laura A Eccles, Jill Tseng, Paulina Cybulska, Monicka Wielgos, Simon N Powell, Douglas A Levine
BRCA1 and BRCA2 are essential for the repair of double-strand DNA breaks, and alterations in these genes are a hallmark of breast and ovarian carcinomas. Other functionally related genes may also play important roles in carcinogenesis. Amplification of EMSY, a putative BRCAness gene, has been suggested to impair DNA damage repair by suppressing BRCA2 function. We employed direct repeat GFP (DR-GFP) and RAD51 foci formation assays to show that EMSY overexpression impairs the repair of damaged DNA, suggesting that EMSY belongs to the family of BRCAness proteins...
January 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/28097883/is-angiotensin-3-4-val-tyr-the-shortest-angiotensin-ii-derived-peptide-opening-new-vistas-on-the-renin-angiotensin-system
#4
Juliana Dias, Flavia Axelband, Lucienne S Lara, Humberto Muzi-Filho, Adalberto Vieyra
Angiotensin-(3-4) (Ang-(3-4) or Val-Tyr) is the shorter angiotensin (Ang) II-derived peptide, formed through successive hydrolysis that culminates with the release of Val-Tyr as a dipeptide. It is formed both in plasma and in kidney from Ang II and Ang III, and can be considered a component of the systemic and organ-based renin-angiotensin system. It is potently antihypertensive in humans and rats, and its concerted actions on proximal tubule cells culminate in the inhibition of fluid reabsorption, hyperosmotic urinary excretion of Na(+)...
January 2017: Journal of the Renin-angiotensin-aldosterone System: JRAAS
https://www.readbyqxmd.com/read/28097633/meropenem-dosing-based-on-a-population-pharmacokinetic-pharmacodynamic-model-in-elderly-patients-with-infection-of-the-lower-respiratory-tract
#5
Qing-Tao Zhou, Bei He, Ning Shen, Ying Liang, Li-Na Sun
BACKGROUND: Meropenem is used for the treatment of severe lower respiratory tract infections (LRTIs) caused by multidrug-resistant Gram-negative bacilli. OBJECTIVE: We evaluated the clinical benefits of a strategy of meropenem dosing based on a population pharmacokinetics/pharmacodynamics (PK/PD) model in elderly patients with an LRTI. METHODS: In this prospective single-center open-label randomized controlled trial, 79 elderly patients with an LRTI caused by Gram-negative bacilli were randomized to a study group (SG) or a control group (CG)...
January 17, 2017: Drugs & Aging
https://www.readbyqxmd.com/read/28089878/pre-transplant-absolute-lymphocyte-counts-impact-the-pharmacokinetics-of-alemtuzumab
#6
Rebecca Marsh, Tsuyoshi Fukuda, Chie Emoto, Lisa Neumeier, Pooja Khandelwal, Sharat Chandra, Ashley Teusink, Alexander Vinks, Parinda A Mehta
Alemtuzumab is frequently used as part of reduced intensity conditioning (RIC) regimens for the allogeneic hematopoietic cell transplantation (HCT) of pediatric patients with non-malignant diseases. We have previously suggested an optimal Day 0 targeted range of alemtuzumab, but there are no pediatric data regarding the pharmacokinetics (PK) of subcutaneous alemtuzumab to guide precision dosing trials. The goal of this study was to prospectively characterize alemtuzumab PK and to explore absolute lymphocyte count (ALC) as a predictor of interindividual variability...
January 12, 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/28087336/oleate-induces-katp-channel-dependent-hyperpolarisation-in-mouse-hypothalamic-glucose-excited-neurones-without-altering-cellular-energy-charge
#7
Selma Dadak, Craig Beall, Julia M Vlachaki Walker, Marc Pm Soutar, Rory J McCrimmon, Michael L J Ashford
The unsaturated fatty acid, oleate exhibits anorexigenic properties reducing food intake and hepatic glucose output. However, its mechanism of action in the hypothalamus has not been fully determined. This study investigated the effects of oleate and glucose on GT1-7 mouse hypothalamic cells (a model of glucose-excited (GE) neurones) and mouse arcuate nucleus (ARC) neurones. Whole-cell and perforated patch-clamp recordings, immunoblotting and cell energy status measures were used to investigate oleate and glucose sensing properties of mouse hypothalamic neurones...
January 9, 2017: Neuroscience
https://www.readbyqxmd.com/read/28078682/population-pharmacokinetics-of-intravenous-clonidine-for-sedation-during-pediatric-extracorporeal-membrane-oxygenation-ecmo-and-continuous-veno-venous-hemofiltration-cvvh
#8
Niina Kleiber, Ron A A Mathôt, Maurice J Ahsman, Enno D Wildschut, Dick Tibboel, Saskia N de Wildt
AIMS: Clonidine is used for sedation in the pediatric intensive care unit. Extracorporeal membrane oxygenation (ECMO) provides temporary support if respiratory and cardiac function is threatened. ECMO influences the pharmacokinetics of drugs. Clonidine during pediatric ECMO cannot be effectively titrated as PK data are lacking. The aim of this study is to describe clonidine PK in a particular ECMO system and propose dosing guidelines for children on this particular ECMO circuit. METHODS: All children below the age of 18 who received clonidine during ECMO were eligible...
January 12, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28076395/mapping-and-genetic-structure-analysis-of-the-anthracnose-resistance-locus-co-1hy-in-the-common-bean-phaseolus-vulgaris-l
#9
Mingli Chen, Jing Wu, Lanfen Wang, Nitin Mantri, Xiaoyan Zhang, Zhendong Zhu, Shumin Wang
Anthracnose is a destructive disease of the common bean (Phaseolus vulgaris L.). The Andean cultivar Hongyundou has been demonstrated to possess strong resistance to anthracnose race 81. To study the genetics of this resistance, the Hongyundou cultivar was crossed with a susceptible genotype Jingdou. Segregation of resistance for race 81 was assessed in the F2 population and F2:3 lines under controlled conditions. Results indicate that Hongyundou carries a single dominant gene for anthracnose resistance. An allele test by crossing Hongyundou with another resistant cultivar revealed that the resistance gene is in the Co-1 locus (therefore named Co-1HY)...
2017: PloS One
https://www.readbyqxmd.com/read/28074265/pharmacokinetic-and-exposure-response-analyses-of-pertuzumab-in-combination-with-trastuzumab-and-docetaxel-during-neoadjuvant-treatment-of-her2-%C3%A2-early-breast-cancer
#10
Angelica L Quartino, Hanbin Li, Jin Y Jin, D Russell Wada, Mark C Benyunes, Virginia McNally, Lucia Viganò, Ihsan Nijem, Bert L Lum, Amit Garg
PURPOSE: The NeoSphere trial evaluated pertuzumab in the neoadjuvant setting [early breast cancer (EBC)] with pathological complete response (pCR) as the primary efficacy end point. This analysis of pertuzumab aimed to (1) compare its pharmacokinetics (PK) in patients with EBC versus advanced cancers, (2) to further evaluate PK drug-drug interactions (DDIs) when given in combination with trastuzumab, and (3) to assess the relationship between exposure and efficacy to assess the clinical dosing regimen in the EBC patients...
January 10, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28074152/optimal-dosage-of-cefmetazole-for-intraoperative-antimicrobial-prophylaxis-in-patients-undergoing-surgery-for-colorectal-cancer
#11
Atsushi Tomizawa, Takatoshi Nakamura, Toshiaki Komatsu, Hiroshi Inano, Rumiko Kondo, Masahiko Watanabe, Koichiro Atsuda
BACKGROUND: Few studies have reported the dosage of cefmetazole (CMZ) for intraoperative antimicrobial prophylaxis in patients underwent surgery for colorectal cancer. We therefore examined the optimal intraoperative dosage of CMZ according to pharmacokinetic/pharmacodynamic (PK/PD) theory in patients who undergoing surgery for colorectal cancer. METHODS: The study group comprised 23 patients with colorectal cancer who underwent surgery, using CMZ as antimicrobial treatment to prevent postoperative infection...
2017: Journal of Pharmaceutical Health Care and Sciences
https://www.readbyqxmd.com/read/28072473/pharmacokinetics-of-obinutuzumab-in-chinese-patients-with-b-cell-lymphomas
#12
John Zhai, Yan Qin, Jun Zhu, Yuqin Song, Zhixiang Shen, Xin Du, Candice Jamois, Michael Brewster, Yuankai Shi, Jun Shi
AIM: The Phase Ib GERSHWIN study (NCT01680991) assessed the pharmacokinetic (PK) profile of obinutuzumab following multiple intravenous (i.v.) doses to Chinese patients with B-cell lymphomas, and compared findings with previous obinutuzumab PK studies in mainly Caucasian (non-Chinese) patients. METHODS: GERSHWIN was an open-label, single-arm intervention study. Patients aged >18 years with CD20+ relapsed/refractory chronic lymphocytic leukaemia (CLL), diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) were enrolled from four centres in China...
January 10, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28063020/evaluation-of-amikacin-pharmacokinetics-and-pharmacodynamics-for-optimal-initial-dosing-regimen
#13
Hideo Kato, Mao Hagihara, Jun Hirai, Daisuke Sakanashi, Hiroyuki Suematsu, Naoya Nishiyama, Yusuke Koizumi, Yuka Yamagishi, Katsuhiko Matsuura, Hiroshige Mikamo
Amikacin has been one of the important antimicrobial agents against Gram-negative pathogens. However, there is discrepancy regarding the amikacin initial dosage, with some reports recently recommending ≥25 mg/kg and others the conventional dosage (15-20 mg/kg). Hence, we evaluated the optimal initial dosing regimen of amikacin. Pharmacokinetic (PK) parameters were estimated using a population PK analysis. The pharmacodynamic (PD) target was a ratio of ≥8 between the concentration achieved 1 h after beginning the infusion (C peak) and the minimal inhibitory concentration (MIC) of the liable bacteria...
January 6, 2017: Drugs in R&D
https://www.readbyqxmd.com/read/28060045/dalbavancin-pharmacokinetics-and-safety-in-children-3-months-to-11-years-of-age
#14
Daniel Gonzalez, John S Bradley, Jeffrey Blumer, Ram Yogev, Kevin M Watt, Laura P James, Debra L Palazzi, Varsha Bhatt-Mehta, Janice E Sullivan, Li Zhang, Jennifer Murphy, Xilla T Ussery, Sailaja Puttagunta, Michael W Dunne, Michael Cohen-Wolkowiez
BACKGROUND: Dalbavancin is a novel lipoglycopeptide antibiotic that has potent in vitro activity against Gram-positive microorganisms. METHODS: We performed a phase 1, open-label, multi-center study to investigate the pharmacokinetics (PK) and safety of a single-dose of intravenous dalbavancin in hospitalized pediatric subjects 3 months to 11 years of age. We combined these data with previously collected adolescent PK data and performed a population PK analysis...
January 3, 2017: Pediatric Infectious Disease Journal
https://www.readbyqxmd.com/read/28059081/aba-unresponsive-snrk2-protein-kinases-regulate-mrna-decay-under-osmotic-stress-in-plants
#15
Fumiyuki Soma, Junro Mogami, Takuya Yoshida, Midori Abekura, Fuminori Takahashi, Satoshi Kidokoro, Junya Mizoi, Kazuo Shinozaki, Kazuko Yamaguchi-Shinozaki
Rapid changes in messenger RNA population are vital for plants to properly exert multiple adaptive responses under continuously changing stress conditions. Transcriptional activation mediated by the 'abscisic acid (ABA)-activated SnRK2 protein kinases-ABA-responsive element (ABRE)-binding proteins/ABRE-binding factors (AREB/ABFs)' signalling module is a crucial step in the expression of stress-inducible genes under osmotic stress conditions in Arabidopsis(1-4). In addition to transcriptional control, proper transcript levels of individual genes can be achieved by post-transcriptional regulation, but how this regulation functions under stress conditions and the underlying molecular mechanisms remain elusive...
January 6, 2017: Nature Plants
https://www.readbyqxmd.com/read/28057922/membrane-translocation-of-t-snare-protein-syntaxin-4-abrogates-ground-state-pluripotency-in-mouse-embryonic-stem-cells
#16
Natsumi Hagiwara-Chatani, Kota Shirai, Takumi Kido, Tomoatsu Horigome, Akihiro Yasue, Naoki Adachi, Yohei Hirai
Embryonic stem (ES) and induced pluripotent stem (iPS) cells are attractive tools for regenerative medicine therapies. However, aberrant cell populations that display flattened morphology and lose ground-state pluripotency often appear spontaneously, unless glycogen synthase kinase 3β (GSK3β) and mitogen-activated protein kinase kinase (MEK1/2) are inactivated. Here, we show that membrane translocation of the t-SNARE protein syntaxin-4 possibly is involved in this phenomenon. We found that mouse ES cells cultured without GSK3β/MEK1/2 inhibitors (2i) spontaneously extrude syntaxin-4 at the cell surface and that artificial expression of cell surface syntaxin-4 induces appreciable morphological changes and mesodermal differentiation through dephosphorylation of Akt...
January 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28045057/conformational-transition-of-fgfr-kinase-activation-revealed-by-site-specific-unnatural-amino-acid-reporter-and-single-molecule-fret
#17
Louis Perdios, Alan R Lowe, Giorgio Saladino, Tom D Bunney, Nethaji Thiyagarajan, Yuriy Alexandrov, Christopher Dunsby, Paul M W French, Jason W Chin, Francesco Luigi Gervasio, Edward W Tate, Matilda Katan
Protein kinases share significant structural similarity; however, structural features alone are insufficient to explain their diverse functions. Thus, bridging the gap between static structure and function requires a more detailed understanding of their dynamic properties. For example, kinase activation may occur via a switch-like mechanism or by shifting a dynamic equilibrium between inactive and active states. Here, we utilize a combination of FRET and molecular dynamics (MD) simulations to probe the activation mechanism of the kinase domain of Fibroblast Growth Factor Receptor (FGFR)...
January 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28038962/confirming-model-predicted-pharmacokinetic-interactions-between-bedaquiline-and-lopinavir-ritonavir-or-nevirapine-in-patients-with-hiv-and-drug-resistant-tuberculosis
#18
Margreke J E Brill, Elin M Svensson, Mishal Pandie, Gary Maartens, Mats O Karlsson
Bedaquiline and its metabolite M2 are metabolised by CYP3A4. The antiretrovirals ritonavir-boosted lopinavir (LPV/r) and nevirapine inhibit and induce CYP3A4, respectively. Here we aimed to quantify nevirapine and LPV/r drug-drug interaction effects on bedaquiline and M2 in patients co-infected with HIV and multidrug-resistant tuberculosis (MDR-TB) using population pharmacokinetic (PK) analysis and compare these with model-based predictions from single-dose studies in subjects without TB. An observational PK study was performed in three groups of MDR-TB patients during bedaquiline maintenance dosing: HIV-seronegative patients (n = 17); and HIV-infected patients using antiretroviral therapy including nevirapine (n = 17) or LPV/r (n = 14)...
December 14, 2016: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/28032946/population-pharmacokinetics-modeling-of-unbound-efavirenz-atazanavir-and-ritonavir-in-hiv-infected-subjects-with-aging-biomarkers
#19
J B Dumond, J Chen, M Cottrell, C R Trezza, Hma Prince, C Sykes, C Torrice, N White, S Malone, R Wang, K B Patterson, N E Sharpless, A Forrest
Unbound drug is the pharmacodynamically relevant concentration. This study aimed to determine if chronologic age or markers of biologic aging, such as the frailty phenotype and p16(INK4a) gene expression, altered unbound pharmacokinetics (PKs) of efavirenz (EFV) and atazanavir/ritonavir (ATV/RTV). Sixty human immunodeficiency virus (HIV)-infected participants receiving EFV and 31 receiving ATV/RTV provided 1 to 11 samples to quantify total and unbound plasma concentrations. Population PK models with total and unbound concentrations simultaneously described are developed for each drug...
December 29, 2016: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28032902/population-pharmacokinetics-of-eplerenone-in-japanese-patients-with-chronic-heart-failure
#20
Masayo Oishi, Yoshiro Tomono, Qinying Zhao, Kevin Sweeney
To characterize eplerenone pharmacokinetics (PK) in Japanese chronic heart failure (CHF) patients and to estimate the impact of factors that may affect eplerenone PK, population pharmacokinetic (PPK) analysis was conducted. In addition, PK of Japanese CHF and Western CHF patients from a previous clinical pharmacology study were compared in the analysis. Eplerenone PK was characterized by a 1-compartment PPK model with first-order absorption and lag time in Japanese CHF patients. The population mean of apparent oral clearance (CL/F) in Japanese CHF patients was estimated as 5...
December 29, 2016: Journal of Clinical Pharmacology
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